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Journal of Virology, December 1999, p. 10158-10163, Vol. 73, No. 12
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Caspase-Dependent N-Terminal Cleavage of Influenza Virus Nucleocapsid Protein in Infected Cells

O. P. Zhirnov,1,* T. E. Konakova,1 W. Garten,2 and H.-D. Klenk2

D. I. Ivanovsky Institute of Virology, 123098 Moscow, Russia,1 and Institute of Virology, Philipps University of Marburg, 35037 Marburg, Germany2

Received 20 May 1999/Accepted 26 August 1999

The nucleocapsid protein (NP) (56 kDa) of human influenza A viruses is cleaved in infected cells into a 53-kDa form. Likewise, influenza B virus NP (64 kDa) is cleaved into a 55-kDa protein with a 62-kDa intermediate (O. P. Zhirnov and A. G. Bukrinskaya, Virology 109:174-179, 1981). We show now that an antibody specific for the N terminus of influenza A virus NP reacted with the uncleaved 56-kDa form but not with the truncated NP53 form, indicating the removal of a 3-kDa peptide from the N terminus. Amino acid sequencing revealed the cleavage sites ETD16*G for A/Aichi/68 NP and sites DID7*G and EAD61*V for B/Hong Kong/72 NP. With D at position -1, acidic amino acids at position -3, and aliphatic ones at positions -2 and +1, the NP cleavage sites show a recognition motif typical for caspases, key enzymes of apoptosis. These caspase cleavage sites demonstrated evolutionary stability and were retained in NPs of all human influenza A and B viruses. NP of avian influenza viruses, which is not cleaved in infected cells, contains G instead of D at position 16. Oligopeptide DEVD derivatives, specific caspase inhibitors, were shown to prevent the intracellular cleavage of NP. All three events, the NP cleavage, the increase of caspase activity, and the development of apoptosis, coincide in cells infected with human influenza A and B viruses. The data suggest that intracellular cleavage of NP is exerted by host caspases and is associated with the development of apoptosis at the late stages of infection.

* Corresponding author. Mailing address: The D. I. Ivanovsky Institute of Virology, Gamaleya Str. 16, Moscow 123098, Russia. Phone: 7-095-190-3058. Fax: 7-095-190-3058. E-mail: zhirnov{at}invir.msk.su.

Journal of Virology, December 1999, p. 10158-10163, Vol. 73, No. 12
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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